Obesity affects an ever-increasing proportion of the population of Western cultures. Nearly one-third of adults in the United States are in excess of their ideal body weight by at least 20%. This results in a major public health problem, because obesity is associated with a multitude of medical problems that include hypertension, elevated blood lipids, coronary artery disease, osteoarthritis and Type II or non-insulin-dependent diabete mellitus (NIDDM). In the United States alone, there are an estimated 6-10 million individuals with NIDDM, including 18% of the population over 65 years of age and most of these individuals are obese (Harris et al. Diabetes 36:523-534, 1987). While there appears to be a heterogeneous etiology for NIDDM, obesity alone leads to insulin resistance and NIDDM in individuals that are predisposed to the disease, and it exacerbates the condition in patients already presenting with NIDDM.
Stability of body composition requires that energy intake equals expenditure when integrated over prolonged periods. Since recent human studies have failed to demonstrate active changes in energy expenditure with changes in body composition, it appears likely that energy intake is continually adjusted to preserve a constant total adipose tissue mass. If adipose tissue mass is regulated directly, then there must be some input signaling this quantity to the central nervous system for the purpose of making corrective changes in appetite when total body fat content fluctuates. The nature of this input has been examined in a variety of animal experiments involving induced weight change (Cohn et al., Yale J. Biol. Med. 34:598-607, 1962; Harris et al., Proc. Soc. Exp. Biol. Med. 191:82-89, 1989; and Wilson et al., Am. J. Physiol. 259:R1148-R1155, 1990); lipectomy (Forger et al., Metabolism 37:782-86, 1988; Liebel et al., Ann. N.Y. Acad. Sci. 131:559-82, 1965; and Chlouverakis et al., Metabolism 23:133-37, 1974); plasma transfer from obese or satiated animals to hungry animals (Davis et al., Science 156:1247-48, 1967; Davis et al., J. Comp. Physiol. Psychol. 67:407-14, 1969; and King, Physiol. Psychol. 4:405-08, 1976); and parabiosis between obese and lean animals (Hervey, J. Physiol. 145:336-52, 1959; Parameswaran et al., Am. J. Physiol. 232:R150-R157, 1977; Nishizawa et al., Am. J. Physiol. 239:R344-351, 1980; Harris et al., Am. J. Physiol. 257:R326-R336, 1989; Schmidt et al., Acta Physiol. Acad. Sci. Hung. Tomus 36:293-98, 1969; Coleman et al., Diabetologia 9:294-98, 1973; Harris et al., Int. J. Obesity 11:275-83, 1987; and Coleman et al., Am. J. Physiol. 217:1298-1304, 1969). From these experiments, there was some evidence that the plasma level of one or more unidentified stable circulating molecules increases in proportion to total body fat content and augments the effect of meal-related satiety signals in the central nervous system.
The search for factors that affect and ultimately control appetite has taken two paths. The first, based on genetic observations, has recently resulted in the cloning of the ob gene (Zhang et al., Nature 372:425-32, 1994; by use of positional cloning using mice that were ob/ob mutants. However, while Zhang and others speculated that the ob gene product may be a regulating factor of body fat content, this has not been shown. The second path involves attempts to isolate a discrete factor or factors that regulate body composition based on functional properties.
The isolation of a functional appetite suppression factor (ASF), however, has been unsuccessful, in part due to an inability to reliably determine changes in food consumption as a result of administration of putative appetite suppression factors. The present invention provides a consistent method for identifying and quantitating ASF activity in a test sample, including a sample containing an expressed ob gene product or other factors that regulate appetite.